Dr. Ky is an adult cardiologist with advanced training in echocardiography and heart failure who is currently enrolled in the Master of Science in Epidemiology program at the University of Pennsylvania. Her long-term goal is to be an independent, patient-oriented physician scientist who will make significant contributions to the study of human cardiac remodeling and cardiovascular medicine. Her career development plan encompasses focused didactic coursework;first hand experience in patient-oriented research through the design and execution of a prospective cohort study and additional cohorts initiated by the candidate;advanced methods in epidemiology and biostatistics for use in two large prospective cohort studies;and a highly structured, cohesive mentoring program. The overall objective of this scientific proposal is to determine the clinical relevance of circulating neuregulin as it relates to ventricular remodeling and risk of adverse clinical outcomes across a broad range of human cardiac remodeling phenotypes. Basic science research has defined this pathway as critical in the maintenance of cardiac function, but whether these findings translate to humans is unknown. Preliminary evidence from the Penn Heart Failure Study (PHFS) suggests that circulating neuregulin-12 (NRG-12) levels may be independently predictive of future risk of death or cardiac transplantation, and this risk may differ significantly by heart failure etiology and severity. Under the direction of Primary mentor Dr. Stephen Kimmel and Co-mentor Dr. Thomas Cappola, Dr. Ky will definitively determine if NRG-12 is associated with clinical outcomes across different etiologies and severity of heart failure and quantify the relationship between NRG-12 and cardiac remodeling over time using two large prospective cohorts: PHFS and the Chronic Renal Insufficiency Cohort (CRIC). Together these cohorts span the entire spectrum of cardiac remodeling, with eccentric hypertrophy in PHFS, and all remodeling geometries, including normal and concentric hypertrophy, in CRIC. The aims of this proposal are to: 1) establish the strength and consistency of the relationship between NRG-12 levels and incident adverse cardiac outcomes in all PHFS patients with eccentric hypertrophy, stratified by etiology and severity;2) determine the longitudinal relationship between NRG-12 and cardiac remodeling in CRIC;3) determine the relationship between NRG-12 and incident cardiac outcomes in CRIC. This research will provide the first large scale, systematic data on circulating neuregulin in human heart disease, laying the foundation for this candidate's long-term goal of translating knowledge from basic science and clinical observations into new approaches to prevent and treat heart failure. The combination of advanced epidemiologic and biostatistical training and mentored, patient-oriented research will ensure Dr. Ky emerges as a highly successful independent investigator in translational cardiovascular research. PUBLIC HEALTH RELEVANCE: Neuregulin is a naturally occurring protein that has beneficial effects on the heart and plays a key role in maintaining heart function in animals. However, human data are lacking. This proposed study, the first of its kind, will translate the compelling animal research to directly relevant findings in humans, by defining the relationships between neuregulin and heart function and outcomes in two large cohorts of human subjects. (End of Absrtract)